Unraveling the tapestry: Lessons from multi-omics and spatial biology in hepatocellular cancer.

Hepatocellular carcinoma (HCC) is a biologically and clinically heterogeneous cancer in which the spatial organization of the tumor microenvironment dictates progression, immune escape, and therapeutic response. Traditional genomic and transcriptomic profiling have revealed key molecular pathways, yet they do not capture the spatial relationships that govern tumor-immune-stromal interactions. Spatial omics technologies now bridge this gap, allowing molecular profiling within intact tissue architecture and revealing how cellular neighborhoods, immune barriers, and stromal niches shape tumor behavior. In this review, we summarize recent advances in technologies like spatial transcriptomics, proteomics, genomics, epigenomics, and metabolomics as applied to HCC. We discuss how these technologies have illuminated the spatial dynamics of the invasive margin, macrophage and fibroblast niches, and immune evasion, identifying both prognostic and predictive biomarkers. We further highlight how spatially resolved analyses have uncovered previously unrecognized axes of communication between cancer cells and key stromal and parenchymal populations that were not apparent from bulk or single-cell molecular analyses alone. These spatially mapped ligand-receptor networks reveal coordinated signaling circuits that define targetable mechanisms of resistance and progression within the microenvironment. Finally, we explore the translational implications where spatial signatures may guide risk stratification, treatment selection, and clinical trial design. By integrating spatial architecture with molecular function, spatial omics is transforming our understanding of liver cancer biology and paving the way for spatially informed precision oncology.